State-of-the-art management of Dravet syndrome.

Raising the bar: Fenfluramine sets new treatment standards for Dravet syndrome

ObjectiveThis study was undertaken to gain consensus from experienced physicians and caregivers regarding optimal diagnosis and management of Dravet syndrome (DS), in the context of recently approved, DS‐specific therapies and emerging disease‐modifying treatments.MethodsA core working group was convened consisting of six physicians with recognized expertise in DS and two representatives of the Dravet Syndrome Foundation. This core group summarized the current literature (focused on clinical presentation, comorbidities, maintenance and rescue therapies, and evolving disease‐modifying therapies) and nominated the 31‐member expert panel (ensuring international representation), which participated in two rounds of a Delphi process to gain consensus on diagnosis and management of DS.ResultsThere was strong consensus that infants 2–15 months old, presenting with either a first prolonged hemiclonic seizure or first convulsive status epilepticus with fever or following vaccination, in the absence of another cause, should undergo genetic testing for DS. Panelists agreed on evolution of specific comorbidities with time, but less agreement was achieved on optimal management. There was also agreement on appropriate first‐ to third‐line maintenance therapies, which included the newly approved agents. Whereas there was agreement for recommendation of disease‐modifying therapies, if they are proven safe and efficacious for seizures and/or reduction of comorbidities, there was less consensus for when these should be started, with caregivers being more conservative than physicians.SignificanceThis International DS Consensus, informed by both experienced global caregiver and physician voices, provides a strong overview of the impact of DS, therapeutic goals and optimal management strategies incorporating the recent therapeutic advances in DS, and evolving disease‐modifying therapies.

Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations From a North American Consensus Panel

Objective: To describe the pharmacology, efficacy, and safety of stiripentol in the treatment of refractory seizures in patients with Dravet syndrome. Data Sources: A search of the English language literature was conducted using PubMed and MEDLINE (1978 to April 2019) with the search terms stiripentol, Dravet syndrome, and refractory epilepsy. Other resources included article bibliographies, prescribing information, and relevant trials at https://clinicaltrials.gov/ . Study Selection and Data Extraction: All phase 1, 2, or 3 trials; observational studies; and retrospective studies were analyzed. Data Synthesis: In controlled studies, stiripentol has been shown to reduce seizure frequency by 50% or more in 40% to 70% of patients with Dravet syndrome. Reductions in seizure duration and episodes of status epilepticus have also been documented. Common adverse effects include somnolence and anorexia. Stiripentol inhibits the metabolism of clobazam and valproate, often requiring dose adjustment. Relevance to Patient Care and Clinical Practice: Stiripentol, a direct allosteric modulator of GABAA receptors, offers a novel approach to treatment in patients with Dravet syndrome, both with and without pathogenic variants of the sodium channel α-1 subunit gene, and potentially other refractory seizures. Although available outside the United States for a decade, it was only recently approved by the Food and Drug Administration for patients 2 years of age and older with Dravet syndrome taking clobazam. Conclusions: Stiripentol is an effective adjunctive therapy for reducing the frequency and duration of refractory seizures in patients with Dravet syndrome. Its role in the treatment of other refractory epilepsies requires further study.

Classic Dravet syndrome is also termed severe myoclonic epilepsy of infancy (SMEI). There are subtle phenotypic variants of Dravet which may have all the features of the syndrome except one, such as without myoclonic seizures, onset in the second year or without generalized spike and wave on EEG. These have been termed borderline variants of SMEI. Rather than ascribing multiple different names to marginally different phenotypes, the term Dravet syndrome is now preferred to describe the group of severe infantile onset epilepsies (OMIM #607208, #182389, #604403) associated with mutations in SCN1A (OMIM *182389). SCN1A-related seizure disorders can be inherited in an autosomal dominant manner but most are due to de novo mutations. SCN1A testing can be done through bi-directional DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) for: 1) individuals with electroclinical phenotype of Dravet Syndrome or clinical sub-types – several seizure types in one individual with onset in infancy, refractory to medication and with generalised spike and wave on EEG, or 2) infants less than 1 year old with 2 or more prolonged hemiclonic febrile seizures in early infancy. Disclaimer: This summary is based on a UK Genetic Testing Network (UKGTN) approved Gene Dossier application.

To report the authors' experience with diagnosis and management of Dravet syndrome, or severe myoclonic epilepsy in infancy, in the era of commercially available genetic testing, the authors performed a retrospective study of 16 patients diagnosed with Dravet syndrome at a tertiary care pediatric epilepsy center. They analyzed their clinical presentation, electroencephalographic findings, genetic (SCN1A gene) results, and treatment responses and compared the findings to previous reports. The patients presented with all the previously described characteristics of Dravet syndrome. Six of the 7 patients (86%) who were tested for SCN1A mutations had positive results. The best treatment combinations included topiramate, valproate, or the ketogenic diet. Dravet syndrome is a well-defined epileptic syndrome that needs larger recognition, particularly because commercial testing for SCN1A gene mutations is now available in the United States. Despite its reputation for seizure intractability, several treatment options may be particularly helpful, whereas others need to be avoided.

Dravet syndrome is a severe developmental and epileptic encephalopathy caused by heterozygous, loss-of-function, pathogenic variants in the SCN1A gene. It is characterized by frequent, often prolonged convulsive seizures. Dravet syndrome is associated with diverse comorbid conditions, including developmental impairment, intellectual disability, and behavioral disturbances, in addition to high mortality rates. Prompt diagnosis and treatment initiation are essential to reduce seizure frequency, status epilepticus, and potentially improve neurodevelopmental outcomes. Currently available therapies such as fenfluramine, stiripentol, and cannabidiol have demonstrated significant reduction in convulsive seizure frequency, based on randomized controlled trials and real-world studies; however, they have not markedly affected non-seizure symptoms. Emerging therapies such as genetic modulation are promising given their potential for disease modification, seizure frequency reduction, and improvement of non-seizure outcomes. This review of observational studies and randomized clinical trials provides an overview of the natural history of Dravet syndrome, current treatment guidelines with recently approved medications, addressing both safety and efficacy, and new therapeutic approaches, including disease-modifying therapies. The therapeutic landscape in Dravet syndrome is evolving, with the use of new antiseizure agents and precision therapies that target the SCN1A variant. Goals of treatment include improvement of seizure burden, neurodevelopment, comorbidities, and quality of life in individuals with Dravet syndrome.

Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. Practically, a patient has epilepsy if having two unprovoked seizures more than 24 hours apart, one unprovoked seizure and significant risk of another seizure, or epilepsy syndrome. Seizures induced by fever do not therefore fit this classification. An initial febrile seizure may therefore cause a false sense of security in children who evolve to febrile seizure plus syndromes. Sodium channel defects seem to predominate as the main causative factor for febrile seizure plus syndromes. More severe pathological variants, such as Dravet's syndrome, have phenotypic similarities to other fever-associated epileptic encephalopathies, including those caused by mutations in protocadherin 19 (PCDH19). The clinical presentations, investigational studies, and management of febrile seizure plus syndrome, as well as epilepsies associated with PCDH19 mutations will be reviewed.

Caregiver impact and health service use in high and low severity Dravet syndrome: A multinational cohort study

Emerging Antiepileptic Drugs for Severe Pediatric Epilepsies

ABSTRACTIntroduction: Dravet syndrome is an early onset epileptic and genetic encephalopathy. Although a well-recognised electroclinical picture is key to diagnosis, a mutation in the SCN1A gene is found in excess of 80%. In general prognosis is poor overall for seizure control and neurodevelopment. With careful phenotyping of the condition and review of treatment response we have become aware of the antiepileptic drugs that are most likely to help, but more importantly drugs that may lead to deterioration and consequently to avoid. Despite this, a significant number of children continue to have seizures and there is little evidence to suggest that we have substantially changed the prognosis in these patients.Areas covered: This review explores current views on the diagnosis and treatment of Dravet syndrome. Consideration is given to the underlying genetics, as well as agents proving to be useful in the management of seizures, including those currently under trial. This has been prepared utilising a review of current literature, as well as expert opinion.Expert opinion: Considerable experience in the field has led to a knowledge of optimised treatment in this condition. This involves both acute and maintenance treatment. Despite this, there has been little impact on overall outcomes. Newer treatments now provide promise with regard to seizure control; whether this will have an impact on overall outcome remains to be seen.

Alterations in metabolic homeostasis can contribute to neuronal hyperexcitability and seizure susceptibility. Although the pivotal role of impaired bioenergetics is obvious in metabolic epilepsies, there is a gap of knowledge regarding secondary changes in metabolite patterns as a result of genetic Scn1a deficiency and ketogenic diet in the Dravet syndrome. A comprehensive untargeted metabolomics analysis, along with assessment of epileptiform activity and behavioral tests, was completed in a Dravet mouse model. Data sets were compared between animals on a control and a ketogenic diet, and metabolic alterations associated with Dravet mice phenotype and ketogenic diet were identified. Hippocampal metabolomic data revealed complex alterations in energy metabolism with an effect of the genotype on concentrations of glucose and several glycolysis and tricarboxylic acid (TCA) cycle intermediates. Although low glucose, lactate, malate, and citrate concentrations became evident, the increase of several intermediates suggested a genotype-associated activation of catabolic processes with enhanced glycogenolysis and glycolysis. Moreover, we observed an impact on the glutamate/γ-aminobutyric acid (GABA)-glutamine cycle with reduced levels of all components along with a shift toward an increased GABA-to-glutamate ratio. Further alterations comprised a reduction in hippocampal levels of noradrenaline, corticosterone, and of two bile acids. Considering that energy depletion can predominantly compromise the function of GABAergic interneurons, the changes in energy metabolism may contribute to seizure susceptibility and ictogenesis. They may also explain the therapeutic potential of the ketogenic diet, which aims to shift energy metabolism toward a more fat-based energy supply. Conversely, the increased GABA-to-glutamate ratio might serve as an endogenous compensatory mechanism, which can be further supported by GABAergic drugs, representing the mainstay of therapeutic management of Dravet syndrome. In view of a possible neuroprotective function of bile acids, it might be of interest to explore a possible therapeutic potential of bile acid-mediated therapies, already in discussion for neurodegenerative disorders.

Introduction—Annual Course 2008: American Epilepsy Society

<p>A critical appraisal and clinical application of Devinsky O, Cross H, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. <em>N Engl J Med</em>. 2017;376(21):2011-2020. doi: <a href="https://doi.org/10.1056/NEJMoa1611618">10.1056/NEJMoa1611618</a>.</p>

Proteomic signature of the Dravet syndrome in the genetic Scn1a-A1783V mouse model